Diabetic cardiomyopathy (DbCM) is characterized by diastolic dysfunction, which progresses into heart failure and aberrant electrophysiology in diabetic patients. Dyslipidemia in type 2 diabetic patients leads to the accumulation of lipid droplets (LDs) in cardiomyocytes and results in lipid toxicity which has been suggested to drive DbCM. It is aimed to explore potential pathways that may boost LDs degradation in DbCM and restore cardiac function. LDs accumulation resulted in an increase in lipid toxicity in DbCM hearts is confirmed. Microlipophagy pathway, rather than traditional macrolipophagy, is activated in DbCM hearts. RNA-Seq data and Rab7-CKO mice implicate that Rab7 is a major modulator of the microlipophagy pathway. Mechanistically, Rab7 is phosphorylated at Tyrosine 183, which allows the recruitment of Rab-interacting lysosome protein (Rilp) to proceed LDs degradation by lysosome. Treating DbCM mice with Rab7 activator ML-098 enhanced Rilp level and rescued the observed cardiac dysfunction. Overall, Rab7-Rilp-mediated microlipophagy may be a promising target in the treatment of lipid toxicity in DbCM is suggested.
As an emerging alternative to perfluorooctanesulfonate (PFOS), 6:2 chlorinated polyfluoroalkyl ether sulfonate (6:2 Cl-PFAES) is associated with male reproductive disorders, yet its testicular targets and mechanisms remain unclear. This study combined in vivo exposure of male C57BL/6J mice (0, 4, 40, and 400 μg/L for 18 weeks) and in vitro assays in primary Leydig cells to demonstrate that 6:2 Cl-PFAES dose-dependently reduced sperm count and serum/testicular testosterone, accompanied by testicular interstitial vacuolation. Transcriptomics and metabolomics demonstrated the concurrent significant enrichment of autophagy pathways and disruption of lipid metabolism. Mechanistically, 6:2 Cl-PFAES suppressed expressions of Sirtuin 1 (SIRT1), ras-related GTP binding protein 7 (RAB7), and deacetylation of forkhead box class O1 (FOXO1), thereby impairing lipophagy flux and promoting lipid droplets accumulation. Molecular docking indicated comparable binding affinity of 6:2 Cl-PFAES and PFOS to SIRT1 (−10.4 kcal/mol), and further research demonstrated that 6:2 Cl-PFAES reduced the deacetylation activity of SIRT1. Crucially, Sirt1 overexpression in transgenic mice (Sirt1TG) or pharmacological activation of SIRT1 (SRT1720) and RAB7 (ML-098) rescued testosterone synthesis and restored lipophagy flux. This study identifies the SIRT1–FOXO1–RAB7 axis as a core target for 6:2 Cl-PFAES-induced suppression of testosterone biosynthesis via lipophagy dysregulation, providing critical molecular insights for assessing the reproductive risks of PFOS alternatives.
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